CZ16093A3 - Sulfonylbenzyl-substituted imidazopyridines - Google Patents

Abstract

Imidazopyridines of the formula (I) <IMAGE> in which R<1> represents alkyl or alkenyl, each of which is optionally substituted by cycloalkyl, or represents cycloalkyl, B and D together form a radical of the formula <IMAGE> A represents a 3- to 8-membered, saturated heterocycle bonded via the nitrogen atom and having up to two further heteroatoms from the group consisting of S, N and O and which is optionally substituted up to 2 times by identical or different perfluoroalkyl having up to 5 carbon atoms or by a radical of the formula <IMAGE> The sulphonylbenzyl-substituted imidazopyridines can be employed as active compounds in medicaments, in particular for the treatment of hypertension and atherosclerosis.

Description

Technical field

The invention relates to sulfonylbenzyl-substituted imidazopyridines, to a process for their preparation and to their use in medicaments, in particular as blood pressure lowering agents and anaatherosclerotic agents.

BACKGROUND OF THE INVENTION

Renin, a proteolytic enzyme, is known to cleave in vivo from angiotensinogen the decapeptide angiotensin I, which again breaks down into the blood pressure-increasing octapeptide angiotensin II in the lungs, kidneys or other tissues. Various effects of angiotensin II, such as vasoconstriction, retention of sodium ions in the kidneys, aldosterone release in the adrenal glands, and an increase in sympathetic nervous system tone, act synergistically in the sense of elevated blood pressure.

In addition, angiotensin II has the property of promoting cell growth and multiplication, such as cardiac muscle and smooth muscle cells, which in many morbidity states (e.g. hypertonia, atherosclerosis and cardiac insufficiency) increase and proliferate.

A possible intervention in the renin-angiotensin system (RAS) is, in addition to inhibiting renin activity, inhibiting angiotensin-converting enzyme (ACE) activity as well as blocking angiotensin II receptors.

The present invention provides sulfonylbenzyl-substituted imidazopyridines of formula (I)

in which

R @ ¹ denotes a straight or branched alkyl or alkenyl group of up to 8 carbon atoms in each case optionally substituted by a cycloalkyl group having 3 to 6 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms,

B and D together form a heterocyclic radical of formula

R ₄ or wherein

R ² and R ³ are identical or different and represent hydrogen, halogen or straight-chain or branched alkyl having up to S carbon atoms,

R ⁴ has the abovementioned meaning of R @ ² and R @ ³ and is identical to or different from this, or represents a group -CO-R, wherein

R ⁶ represents a hydroxy group, a straight or branched alkoxy group having up to 8 carbon atoms, a phenoxy group, a benzyloxy group or an -NR ⁷ R ^{8 group} , wherein:

R ⁷ and R ⁸ are the same or different and denote a hydrogen atom, a straight or branched alkyl group of up to 6 carbon atoms or a phenyl group,

R represents a hydrogen atom, a halogen atom, a straight or branched alkyl group of up to 8 carbon atoms, or a straight or branched perfluoroalkyl group of up to 6 carbon atoms, or a group of the formula -ΟΧ, wherein:

X represents a hydrogen atom, a hydroxy protecting group or a straight or branched alkyl group of up to 8 carbon atoms, and

A denotes a 3 to 8 membered saturated heterocycle with up to 2 additional heteroatoms selected from the group consisting of sulfur, nitrogen or oxygen, which is optionally up to twice the same or differently substituted by a perfluoroalkyl group of up to 5 carbon atoms or a radical of formula

CO-R ¹⁰ or -? (OR ¹¹ ) (OR ¹² ), wherein

R represents a hydrogen atom, a straight or branched alkyl group having up to 6 carbon atoms, or a triphenylmethyl group,

R ¹⁰ is as defined above for R ⁶ and is the same or different with R 12

R a are the same or different and represent a hydrogen atom, a straight or branched alkyl group of up to 8 carbon atoms or a phenyl group, and salts thereof.

The sulfonylbenzyl-substituted imidazopyridines of the present invention may also exist in the form of their salts. In general, salts with organic or inorganic bases or acids can be mentioned.

Physiologically acceptable salts are preferred within the scope of the present invention. Physiologically acceptable salts of sulfonylbenzyl-substituted imidazopyridines can be salts of the compounds of the present invention with mineral acids, sulfonic acids or carboxylic acids. Particularly preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid citric acid, fumaric acid, maleic acid or benzoic acid.

Physiologically acceptable salts also include metal or ammonium salts of the compounds of the present invention having a called carboxyl group. Particularly preferred are, for example, sodium salts, potassium salts, magnesium salts or calcium salts, as well as ammonium salts derived from ammonia or organic amines, such as ethylamine, diethylamine, triethylamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine. .

The compounds of the present invention may exist in stereoisomeric forms that behave either as an image and a mirror image (enantiomers) or not as an image and a mirror image (diastereomers). The present invention relates to both antipodes and racemic forms as well as diastereomeric mixtures. Racemic forms, like diastereomers, can be resolved into stereoisomerically uniform components by known methods (see E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962).

A 3- to 8-membered saturated heterocycle bonded through a nitrogen atom and which may additionally contain as heteroatoms up to two oxygen, sulfur and / or nitrogen atoms is generally azetidinyl, piperidyl, morpholinyl, piperazinyl or pyrrolidinyl. Preferred are 5- and 6-membered rings with one oxygen atom and / or up to two nitrogen atoms, such as azetidinyl, piperidyl, morpholinyl, piperazinyl or pyrrolidinyl. Piperidyl and pyrrolidinyl are particularly preferred.

The hydroxy protecting group within the definition is general protecting groups selected from the group consisting of:

trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triphenylsilyl, trimethylsilylethoxycarbonyl, benzyl, triphenylmethyl (trityl), dimethoxytrityl) (DMT) trityl , 2-nitrobenzyl, 4-nitrobenzyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, 4-methoxybenzyl, 4-methoxybenzyloxycarbonyl, ethyl, formyl, , 2,2-trichloroethoxycarbonyl, 2,4-dimethoxybenzyl, 2,4-dimethoxybenzyloxycarbonyl, methoxymethyl, methylthiomethyl, methoxyethoxymethyl, [2- (trimethylsilyl) ethoxy j) methyl, 2- (methylt) hiomethoxy) ethoxycarbonyl, tetrahydropyranyl, benzoyl, 4-methylbenzoyl, 4-nitrobenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl and 4-methoxybenzoyl. Acetyl, benzyl and tert-7 are preferred

a butyldimethylsilyl group.

Preferred are compounds of formula I wherein:

R @ ¹ denotes a straight or branched alkyl or alkenyl group having in each case up to 6 carbon atoms optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or cyclopropyl, cyclopentyl or cyclohexyl,

B and D together represent a heterocylic radical of the formula

in which

R 3 and R 3 are the same or different and represent a hydrogen atom, a fluorine, chlorine or bromine atom, or a straight or branched alkyl group of up to 6 carbon atoms, and

9 7

R is as defined for R ^4, and R is the same or different with or denotes a group of the formula -CO-R ⁶ , wherein:

R ⁶ represents a hydroxy group, a straight or branched alkoxy group having up to 6 carbon atoms, a phenoxy group, a benzyloxy group or a group of the formula -NR ⁷ R ⁸ , wherein:

8

R and R0 are the same or different and denote a hydrogen atom or a straight or branched alkyl group having up to carbon atoms,

R ⁵ represents a hydrogen atom, a fluorine, chlorine or bromine atom, a straight or branched alkyl group having up to 6 carbon atoms, or a straight or branched perfluoroalkyl group having up to 4 carbon atoms, or a group of the formula -ΟΧ,

X represents a hydrogen atom, a benzyl group, an acetyl group or a straight or branched alkyl group of up to 6 carbon atoms, and

A represents an azetidinyl group bonded via a nitrogen atom to a piperidinyl group, a pyrrolidinyl group or a morpholinyl group, which are optionally substituted with a trifluoromethyl group or a radical of formula

Á 5?

-SO ₃ H, ^N x Q -Lr, -CO-R ¹⁰ or -P (OR ¹¹ ) (OR ¹² ),

N-N wherein

Q

R represents a hydrogen atom, a straight or branched alkyl group having up to 4 carbon atoms, or a triphenylmethyl group,

R ¹⁰ is as defined above for R ⁶ and the same or different thereof;

R ¹¹ and R ¹² may be the same or different and represent a hydrogen atom, a straight or branched alkyl group of up to 6 carbon atoms or a phenyl group, and salts thereof.

Particularly preferred are compounds of formula 1 wherein:

R @ ¹ denotes a straight or branched alkyl or alkenyl group of up to 4 carbon atoms or a cyclopropyl group,

B and D together represent a heterocyclic radical of the formula

«4 in which

3 ·

R‘ and R jsou are the same or different and are a hydrogen atom, a fluorine, chlorine or bromine atom, or a straight or branched alkyl group of up to 4 carbon atoms, and

R ⁴ has the meaning stated for R ² and R ³ and is identical to or different from this, or represents a group of formula

-CO-R ^6, wherein

R ⁶ represents a hydroxy group, a straight or branched alkoxy group having up to 4 carbon atoms, a phenoxy group, a benzyloxy group or a group of the formula -NR ⁷ R ⁸ , wherein:

R and R are the same or different and denote a hydrogen atom or a straight or branched alkyl group having up to carbon atoms,

R represents a hydrogen atom, a fluorine or chlorine atom, a straight or branched alkyl group of up to 4 carbon atoms, or a straight or branched perfluoroalkyl group of up to 3 carbon atoms, or a group of the formula -ΟΧ, wherein:

X represents a hydrogen atom, a benzyl group, an acetyl group or a straight or branched alkyl group of up to 6 carbon atoms, and

A represents an azetidinyl group bonded via a nitrogen atom to a piperidinyl group, or a pyrrolidinyl group, which are optionally substituted with a trifluoromethyl group or a radical of formula

And?

-SO ₃ H, NOA _n , -CO-R ¹⁰ or -P (OR ¹¹ ) (OR ¹² ),

NN ⁹ where

R ⁹ represents a hydrogen atom, a methyl group, an ethyl group or a triphenylmethyl group,

R ¹⁰ has the meaning given above for R ^a and is identical or different and

² · R ¹ and R ¹² may be the same or different and denote hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or phenyl, and salts thereof.

The present invention further provides a process for the preparation of compounds of the formula I which comprises reacting sulfonylbenzyl compounds of the formula II

LH ₂ C // r ₅

so ₂ -a in which A and R R are as defined above, and

L represents a halogen atom, preferably bromine, with the imidazopyridines of the general formula III

Λ (ΙΠ), in which R ^, B and D are as defined above, in inert solvents and in the presence of a base and both the R ^ and R ³ substituents as well as the heterocyclic rings (A, B, D) may optionally be converted by conventional methods such as alkylation or saponification.

The process of the present invention can be illustrated by the following reaction scheme.

NaH Oh ₂

-►

DMF C |

0 ₂ S

CO ₂ -C (CH ₃ ) ₃

N- <

Suitable solvents for this process are the customary organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran or glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halohydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichlorethylene, trichloroethane, trichloride chlorobenzene, and ethyl acetate, triethylamine, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Tetrahydrofuran, methylene chloride, toluene or dimethylformamide is preferred for the various steps.

Suitable bases for the process according to the invention are generally inorganic or organic bases. These preferably include alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as carbonate calcium alcoholates or alkali metal amides or alkaline earth metals, such as sodium methanolate or potassium methanolate, sodium or potassium tert-butylate, sodium or potassium or lithium diisopropylamide (LDA), or organic amines (trialkyl / C | -C _g / amines ), such as triethylamine, or heterocycles, such as 1,4-diazabicyclo [2.2.2] octane (DABCO),

1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. Alkali metals such as sodium or hydrides thereof such as sodium hydride may also be used as bases. Sodium hydride, lithium diisopropylamide (LDA) and DBU are preferred.

In general, the bases are used in an amount of 0.05 mol to 10 mol, preferably 1 mol to 2 mol, based on 1 mol of the compound of the general formula III.

The process of the present invention is generally carried out at a temperature in the range of -100 ° C to 100 ° C, preferably 0 ° C to 30 ° C.

The process according to the invention is generally carried out at normal pressure, but it is also possible to work at elevated or reduced pressure, for example in the range of 0.05 to 0.5 MPA.

Suitable bases for saponification are conventional inorganic bases. These preferably include alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate or sodium bicarbonate, or alkali metal alcoholates such as sodium methoxide , sodium ethanolate, potassium methanolate, potassium ethanolate or potassium tert-butanolate. Sodium hydroxide or potassium hydroxide is particularly preferred.

Suitable solvents for the saponification are water or the organic solvents customary for saponification. These include preferred alcohols such as methanol, ethanol, propanol, isopropanol or butyl alcohol, or ethers such as tetrahydrofuran or dioxane, or dimethylformamide and dimethylsulfoxide.

Alcohols such as methanol, ethanol, propanol or isopropanol are particularly preferred. It is also possible to use mixtures of the solvents mentioned.

The saponification can also be carried out with acids such as trifluoroacetic acid, acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, sulfuric acid or perchloric acid, preferably with trifluoroacetic acid.

The saponification is generally carried out at a temperature in the range of 0 ° C to 100 ° C, preferably 20 ° C to 80 ° C.

In general, the saponification is carried out under normal pressure, but it is also possible to operate under reduced or elevated pressure, for example in the range of 0.5 to 5 bar.

In carrying out the saponification, the base is generally used in an amount of 1 to 3 mol, preferably 1 to 1.5 mol, based on 1 mol of the ester. Molar amounts of the reactants are particularly preferably used.

In carrying out the reaction, carboxylates of the compounds of the present invention are formed in the first step as intermediates which can be isolated. The acids of the present invention are obtained by treating the carboxylates with conventional inorganic acids. These preferably include mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.

In the production of carboxylic acids, it has proven advantageous to acidify the basic reaction mixture of the saponification in the second step without isolating the carboxylates. The acids can then be isolated by conventional means. In the case of basic heterocycles, treatment of carboxylate solutions with the above acids can also yield salts of heterocycles with inorganic acids

The alkylation is in general carried out using alkylating agents such as alkyl halides having 1 to 6 carbon atoms, sulphonic acid esters or substituted or unsubstituted (C ^^ - Cg) -dialkylsulf sulfates or (C ₁ -C ₅₎ -diarylsulfáty, preferably methyl iodide or dimethylsulfate.

The alkylation is generally carried out in one of the abovementioned solvents, preferably dimethylformamide, at a temperature in the range of 0 ° C to 70 ° C, preferably 0 ° C to 30 ° C, and at normal pressure.

The compounds of formula (II) are novel and can be prepared, for example, by reacting compounds of formula (IV) when R @ ^{5 is} not -ΟΧ.

in which L is as defined above and

is as defined above for R ³ , with compounds of formula V (V) in which A is as defined above, in one of the above solvents and in the presence of a base, preferably dichloromethane with triethylamine, at normal pressure and at a temperature in the range of 40 ° C to 120 ° C, preferably at 0 ° C, and when R ⁵ is -ΟΧ, starting from carboxy, hydroxy-disubstituted benzenesulfonic acid chlorides such as 4-carboxy-3-hydroxybenzenesulfochloride wherein the reaction with compounds of formula V first produces compounds of formula VI (X = Η),

HIM

HIM.

in which A is as defined above, then by converting the carboxyl function to the corresponding benzyl ester and blocking the hydroxyl function by conventional methods, they are converted to compounds of formula VII • H2CO-C.

sc ₂ -a οχ · (VII) wherein A is as defined above and a

X 'has the meaning given above for X but does not indicate a hydrogen atom, the next step also reduces the benzyl ester, preferably with sodium hydride / LiCl in diglyme, to hydroxymethyl function in a known method, and finally brominates with triphenylphosphine dibromide in one of the above solvents, preferably dimethylformamide, under a protective gas atmosphere and at a temperature in the range of 0 ° C to room temperature.

The compounds of formulas VI and VII are novel and can be prepared by the methods described above.

The compounds of formulas IV and V are known or can be prepared by methods known per se.

The compounds of formula III are also known per se.

The foregoing methods of manufacture are given for clarity only. The preparation of the compounds of the present invention of formula (I) is not limited to these processes, any modification of these processes being equally applicable to the production.

The compounds of the formula I according to the invention are distinguished by an unforeseeable, valuable pharmacological spectrum of action.

The compounds of the present invention have a specific A II-antagonistic effect since they inhibit the binding of angiotensin II to A II receptors. They suppress the vasoconstrictor and aldosterone secretion-stimulating effects of angiotensin II. In addition, they inhibit the proliferation of smooth muscle cells.

Thus, the compounds can be used for the treatment of arterial hypertonia and atherosclerosis. In addition, they can be used for the treatment of coronary heart disease, cardiac insufficiency, brain tension disorders, ischemic brain disorders, peripheral blood circulation disorders, renal and adrenal disorders, bronchospastic and vascular diseases of the respiratory tract, sodium retention and swelling.

In addition, the substances have a natriuretic and diuretic effect. This effect is manifested in leaching of the edema at the pathological increase in the amount of liquid of cardiac and non-cardiac origin.

Assay for blockade of agonist contractions

Rabbits of both sexes were sacrificed by a wound to the ligament and exsanguinated or possibly killed by anesthesia with Nembutal (ca. 60-80 mg / kg i.v.) by opening the thorax. The thorax aorta was excised and de-adhered, cut into 1.5 mm annular segments and treated in an initial load of about 3.5 g in a 10 ml Krebs-Henseleit nutrient solution saturated with carbon dioxide and tempered to 37 ° C. ° C, having the following composition:

119 mmol / l NaCl

2.5 mmol / l 1.2 mmol / l 10 mmol / l

4.8 mmol / l

CaCl ₂ x 2 H ₂ 0 kh ₂ to ₄ glucose

KC1

1.4 mmol / l MgSO ₄ x 7 H ₂ O and mmol / l NaHCO ₃ .

Contractions were recorded isometrically on Satham UC2-Zellen via a bridge amplifier (ifd Mülheim or DSM Aalen) and digitized and evaluated using an A / D-Wandler (System 570, Keithley, Miinchen). The evaluation of agostin effect curves (DWK) is performed hourly. For each DWK, 3 or 4 individual concentrations were applied to the bath at 4 minute intervals. After the end of the DWK and subsequent wash cycles (sixteen times at 5 s / min each with the above nutrient solution), the 28-minute resting or incubation phase ends, during which the contractions generally return to baseline again.

Those values that normally belonged to the 3rd DWK were used as comparative values for the evaluation of the substances tested in the subsequent course, which were applied to the baths at increasing doses from the beginning of the incubation for the following DWKs. Each aortic ring was always stimulated with the same agonist throughout the day.

Agonists and their standard concentrations (application rate for single dose = 100 μΐ)

KC1 22.7; 32.7, 42.7, 52.7 mmol / l 1-noradrenaline 3x10 ~ ⁹ ; 3x10 ~ ⁸ ; 3x10 ^-7 ; 3x10 ~ ⁶ ; g / ml serotonin 10 ~ ⁸ ; 10 ~ ⁷ ; 10 ~ ⁶ ; 10 ~ ⁵ g / ml B-HT 920 ⁷ “ ⁷ ; ΙΟ ⁶ ; 10 ^-5 g / ml methoxamine ΙΟ ^-7 ; ΙΟ ^-6 ; 10 ^-5 g / ml angiotensin II 3x10 ^-9 ; 10 ~ ⁸ ; 3x10 ~ ⁸ ; 10 ^-7 g / ml.

For the calculation of IC 50 (the concentration at which the test substance causes 50% inhibition), the effect is always 3 submaximal agonist concentrations.

The compounds of the present invention inhibit angiotensin II-induced contraction of isolated rabbit aorta. These contractions, induced by potassium depolarization or other agonists, were not inhibited at all or only weakly at high concentrations.

Table A

Inhibition of vascular contractions in vitro on isolated rabbit aortic rings

IC _5Q [ηΜΓ with contractions induced by:

eg. no. AII IC _5Q [ηΜΓ

5 40 2 326 19 Dec 6 20 May 6 31 4 39 3 41 3

Blood pressure measurement in rats infused with angiotensin II

Male Wistar rats (Moellegaard, Kopenhagen, Denmark) weighing 200-350 g were anesthetized with thiopental (100 mg / kg i.p.). Following tracheotomy, a blood pressure catheter was inserted into the femoral artery and one angiotensin II infusion catheter and a substance delivery catheter into the femoral vein. Angiotensin II infusion (0.3 μg / kg / min) was started following a dose of pentolinium ganglioblocator (5 mg / kg i.v.). Once the blood pressure values have reached a stable level, the test substance is administered intravenously or orally as a suspension or solution in 0.5% Tylose. Changes in blood pressure due to test substances are presented in Table B as mean ± SEM.

Table B

Example mg / kg p.o. measuring blood. pressure

20 May 0.1 -48 mm Hg 31 0.1 -62 mm Hg 39 0.1 -32 mm Hg

Determination of antihypertensive effect on uncontrolled hypertensive rats

The oral antihypertensive activity of the compounds of the present invention was tested in non-clogged rats in which unilateral renal artery stenosis was surgically induced. To this end, the right kidney artery was narrowed by a silver push-button with a diameter of 0.18 mm. In this form of hypertonia, plasma renin activity is increased in the first six weeks after intervention.

The arterial blood pressure of these animals was measured at defined time intervals by bloodless cuff in the tail vein. The test substances were administered in various doses by means of an esophageal probe intragastrally (orally) dispersed into a tylosis suspension. The compounds of the present invention reduce the arterial blood pressure of hypertensive rats at a clinically relevant dosage.

In addition, the compounds of the present invention inhibit dose-specific binding of radioactive angiotensin II in a dose-dependent manner.

Interactions of compounds of the invention with angiotensin II receptor on adrenal cortex membrane fractions (cattle)

The bovine adrenal cortex, which was freshly removed and carefully removed from the pulp, was further pulverized in glucose solution (0.32 M) with Ultra-Turrax (Janke & Kunkel, Staufen iB) to coarse membrane homogenate and partially purified to two centrifugation stages. membrane fraction.

Receptor binding experiments were performed on partially purified bovine adrenal cortex membrane fractions with radioactive angiotensin II in 0.25 ml test chambers, each containing partially purified membranes (50-80 µg), ³ H-angiotensin II (3 - 5 nM) and assay buffer (50 mM Tris, pH 7.2, mM MgCl ₂ 0.25% BSA) of the test substance. After an incubation period of 60 minutes at room temperature, unbound radioactivity of the samples was separated using a moistened glass24 filter (Whatman GF / C) and the bound radioactivity was measured after washing the protein with ice buffer (50 mM Tris / HCl pH 7.4, 5% PEG 6000). spectrophotometrically in a scintillation cocktail. The raw data analysis was performed using a computer program for Kf and IC ₅₀ values, respectively (K _± : IC ₅₀ values corrected for the radioactivity used; IC ₅₀ : concentration at which the test substance showed 50% inhibition of specific radioligand binding).

? ř. 5 Kf = 550 nM

Ex. 2 Kf = 1000 nM

Investigation of inhibition of smooth muscle cell proliferation by the compounds of the invention

Smooth muscle cells obtained from aortic rats and pigs using the Media-Explantat technique (R. Ross, J. Cell. Biol.

50, 172 (1971). Cells were seeded in suitable culture dishes, typically 24-hole dishes, and cultured for 2-3 days in medium 199 with 7.5% FCS and 7.5% NCS, 2 mM Lglutamine and 15 mM HEPES and pH 7.4 in 5% CO ₂ at 37 ° C. Thereafter, the cells were synchronized with serum extract for 2-3 days and then stimulated to grow with angiotensin II, serum or other factors. Test compounds are added simultaneously. After 16-20 hours 1 (iCi ³ H-thymidine) was added and after a further 4 hours the incorporation of these substances into TCA-precipitatable DNA cells was determined.

Example of inhibition at 10

70

40

Test of natriuretic effect

Wistar fasting rats were orally dosed with the test substance (suspended in tylosin solution). Urine excreted is then collected for 6 hours. Urine sodium and potassium concentrations are determined by flame photometry.

The novel active compounds can be converted into conventional preparations such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions using known methods, using inert, non-toxic and pharmaceutically acceptable carriers or solvents. Therapeutically active compounds are to be present in a concentration of about 0.5 to 90% by weight of the total composition, i.e. in an amount sufficient to achieve the dosage range indicated.

For example, the preparations are prepared by mixing the active ingredient with solvents and / or carriers, optionally using emulsifying agents and / or dispersing agents, whereby, for example, if water is used as a diluent, organic solvents may optionally be used as co-solvents.

Administration is effected by conventional means, preferably orally or parenterally, in particular perlingually or intravenously

For parenteral administration, solutions of the active ingredient using suitable liquid carrier materials can be used.

In general, it has proven advantageous to administer an amount of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg body weight, for intravenous administration to achieve effective results. For oral administration, the dosage is about 0.01 to 20 mg / kg, preferably 0.1 to 10 mg / kg body weight.

Nevertheless, it may be necessary to dispense with the above amounts, depending on the body weight or the type of administration, but also on the individual tolerance to the medicament, the type and type of preparation and the time or interval at which the administration takes place. Thus, it may be sufficient in individual cases that starting from less than the above-mentioned minimum doses, while in other cases those upper limits will have to be exceeded. In the case of administration of larger amounts, it is advisable to divide this dose into a number of individual doses during the day.

DETAILED DESCRIPTION OF THE INVENTION

Starting compounds

Example I

4- (Bromomethyl) benzenesulfochloride

5r

8.1 g (0.2 mol) of 4-methylbenzenesulfonyl chloride are dissolved in 300 ml of carbon tetrachloride, mixed with 35.6 g (0.2 mol) of N-bromosuccinimide and after addition of 0.2 g (1.2 mol) Azo-bis-isobutvronitrile (ABU) was heated to reflux for 4 hours. After cooling, the solid was filtered off and the filtrate was freed from solvent. Flash chromatography (petroleum ether / toluene 4: 1, particle size 50 µm) followed by crystallization from 100 ml of cyclohexane gave 24.0 g (45% of theory) of the title compound.

Rf = 0.75 (toluene).

Example II

4- (Sromomethyl) -3-chlorobenzenesulfon chloride

Cl

45.9 g (0.2 mol) of 3-chloro-4-methylbenzenesulfonic acid are mixed with 83.3 g (0.4 mol) of phosphorus pentachloride and the reaction mixture is heated for 30 minutes at an oil bath temperature of 140 ° C. Toluene (500 ml) was added hot, the solution was heated to boiling and poured onto ice after cooling. The organic phase was separated and washed with water (2 x 200 mL). After drying over anhydrous magnesium sulfate, it is filtered and all volatile components are drawn off under vacuum. The residue thus obtained is purified by flash chromatography (pertolether / toluene 4: 1, particle size 50 μη). It is obtained as follows

24.9 g of product which is immediately reacted further.

The product is taken up in 200 ml of carbon tetrachloride and refluxed for 6 hours after addition of 19.6 g (0.11 mol) of N-bromosuccinimide and 0.1 g (0.6 mmol) of ASN. After cooling, the solid was filtered off and the filtrate was freed from solvents. Flash chromatography (petroleum ether / toluene 4: 1, particle size 50 μη) gave 21.2 g (35% of theory) of the title compound.

Rf = 0.32 (petroleum ether / dichloromethane 4: 1).

Example III

4- (bromomethyl) -benzenesulfonyl-N-pyrrolidinide

Br-H ₂ C

N /

S0 ₂

5.3 g (0.02 mol) of the compound of Example I are dissolved in 200 ml of dichloromethane and 4.0 g (0.04 mol) of toluene and after addition of 1.4 g (0.02 mol) of pyrrolidine in 50 ml of dichloromethane at 0 ° C, the reaction mixture was stirred at 0 ° C for one hour. It was then extracted with 2N hydrochloric acid (2 x 100 ml) and water (2 x 100 ml), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to remove all volatiles.

Yield: 5.4 g (89% of theory)

_Rf = 0.09 (toluene).

Example IV

4- (Sromomethyl) -benzenesulfonyl-N-piperidinide

Analogously to Example III, 1.0 g (81% of theory) of the title compound was obtained from 1.1 g (4 mmol) of the compound of Example I and 0.34 g (4 mmol) of piperidine.

Rf = 0.14 (toluene).

Example V (S) -4- (Sromomethyl) -benzenesulfonyl-N-2- (tert-butoxycarbonyl) pyrrolidinide

Analogously to Example III, it is obtained from

7.25 g (27 mmol) of the compound of Example I and 4.6 g (27 mmol) of S-proline-tert-butyl ester 9.1 g (84% of theory) of the title compound.

Rf = 0.66 (petroleum ether / ethyl acetate 7: 3).

Example VI rac. 4- (Sromomethyl) -benzenesulfonyl-N-2- (tert-butoxycarbonyl) -piperidinide

Analogously to Example III, 7.4 g (59% of theory) of racec-tert-butyl ester of pipecolinic acid are obtained from 8.0 g (30 mmol) of the compound of Example I and 5.5 g (30 mmol). of the title compound.

Rf = 0.53 (petroleum ether / ethyl acetate 5: 1).

Example VII (S) -4- (Sromomethyl) -3-chlorobenzenesulfonyl-N-2- (tert-butoxycarbonyl) pyrrolidinide

Cl

Analogously to Example III, 13.9 g (96 of the title compound) of 10.0 g (33 mmol) of the compound of Example II and (33 mmol) of S-proline tert-butyl ester were obtained.

Rf = 0.55 (petroleum ether / ethyl acetate 7: 3).

Example VIII rac. -4- (Bromomethyl) -3-chlorobenzenesulfonyl) -N-2- (tert -carbonyl) piperidinide

5.7 g of theory), but analogously to Example III, from 10.0 g (33 mmol) of the compound of Example II and rac. target. butyl ester of pipecolinic acid (14.6 theory) of the title compound.

Rf = 0.6 (petroleum ether / ethyl acetate 7: 3).

Example IX

N-Jifluoroacetyl-L-prolinamide obtains / 1 g (98%)

Trifluoroacetylproline (0.142 mol) was placed under 150 ml of dimethylformamide under protective atmosphere. 142.6 ml (0.1704 mol) of 38% phosphorus pentoxide in ethyl acetate are added at -20 ° C and ammonia is introduced until saturation, a white precipitate precipitates after 30 minutes. . The batch is then added to 600 ml of water and acidified with concentrated acetic acid to pH 4 and the mixture is shaken four times with 200 ml of methylene chloride and three times with 300 ml of diethyl ether each time. The combined organic phases were dried over anhydrous magnesium sulfate and the solvent was stripped off. The obtained residues are co-chromatographed on silica gel 60 F 254 (methylene chloride / methanol 10: 1). The product containing fractions was freed from the solvents on a rotary evaporator. Yield: 17.12 g (57%) of the title compound R _f = 0.345 (T / EA / _CH3 COOH 20: 20: 1).

Example X

2-Cyano-N-trifluoroacetyl-pyrrolidine

g (0.19 mol) of the product of Example XVI and 45 g (46 ml = 0.57 mol) of pyridine are introduced into 300 ml of tetrahydrofuran under a protective gas atmosphere. At 0 ° C, 48 g = 32.25 ml (0.228 mol) of trifluoroacetic anhydride are added dropwise and the reaction mixture is stirred for 30 minutes at 0 ° C and then for 90 minutes at room temperature. The batch is then transferred to one liter of 1N hydrochloric acid and shaken three times with 200 ml of methylene chloride each time. The combined organic phases are shaken with 200 ml of saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was then stripped off and the residue was chromatographed on silica gel 60 F 254 using a mixture of petroleum ether, ethyl acetate and acetic acid (1600: 200: 5). The fractions containing product were concentrated to give 32.4 g (88.8% of theory) of the title compound.

_Rf = 0.57 (PE / EA 7: 3).

Example XI

2-Tetrazolyl-N-trifluoroacetyl-pyrrolidine

31.35 g = 32.6 ml (0.26 mol) of diethylaluminum chloride are introduced into 65 ml of toluene under a protective gas atmosphere. 29.95 g = 34.04 ml (0.24 mol) of trimethylsilyl azide are added at room temperature and stirred for 10 minutes at room temperature. 25 g (0.13 mol) of the product of Example XVII, dissolved in 65 ml of toluene, are added at 0 ° C and the reaction mixture is stirred for 30 minutes at 0 ° C, for 120 minutes at room temperature and 60 minutes at 40 ° C. The cooled batch is then mixed with saturated potassium fluoride solution until no more gas evolution is observed.

The reaction mixture is taken up in 600 ml of water, acidified to pH 4 and extracted three times with 100 ml of ethyl acetate in each case. The combined organic phases are mixed with 50 ml of n-hexane. To remove the azides, about 1/3 of the solvent is distilled off through a distillation bridge without cooling. The residue was dried over anhydrous magnesium sulfate and stripped of solvents on a rotary evaporator. 18.54 g (60.6% of theory) of the title compound are obtained.

_Rf = 0.4 (toluene / ethyl acetate 1: 1).

Example XII

N-trifluoroacetyl-2- (N-trityl-tetrazolyl) pyrrolidine

N-N

N

o cf ₃

16.23 g (0.069 mol) of the product of Example XI and 10.47 g = 14.35 ml (0.1035 mol) of triethylamine are introduced into 70 ml of methylene chloride and 19.83 g (0.069 mol) of triphenylmethyl chloride are added. The reaction mixture was allowed to stir for 1.5 hours at room temperature, diluted with methylene chloride and extracted with pH = 5 buffer solution (3 x 50 mL). The organic phase was dried over anhydrous magnesium sulfate. The solvent is then removed on a rotary evaporator, the residue is stirred with diethyl ether and the precipitated crystals are filtered off with suction and dried. 24.65 (75% of theory) of the title compound are obtained.

Rf = 0.53 (petroleum ether / ethyl acetate 7: 3).

Example XIII

2- (N-Frityl-tetrazolyl) pyrrolidine

N-N

g (0.05 mol) of the product of Example XII are introduced into 100 ml of ethyl alcohol under a protective gas atmosphere. Sodium borohydride (2.84 g, 0.075 mol) was added portionwise at 0 ° C. The batch was aspirated and stirred for one hour at room temperature. It is then mixed with 6 ml of acetic acid and the whole reaction mixture is added to 500 ml of a buffer solution of pH 9. The batch is extracted three times with 75 ml of methylene chloride each time, the combined organic phases are dried over anhydrous magnesium sulphate and freed from the solvent on a rotary evaporator. The residue is chromatographed on silica gel 60 F 254 using a 7: 3 mixture of petroleum ether and ethyl acetate and the corresponding fractions are concentrated and dried. 7.16 g (37.5% of theory) of the title compound are obtained.

Rf = 0.22 (ethyl acetate).

Example XIV

4-Bromomethyl-3-chloro-benzenesulfonic acid 2- (frityl-tetrazolyl) pyrrolidinide

(^ 6 ^ 5)

Analogously to Example III, 3.19 g (10.5 mmol) of the compound of Example II and g (10.5 mmol) of the compound of Example XX (6.49 g of theory) in the title compound.

Rf = 0.53 (petroleum ether / ethyl acetate 7: 3).

Example XV is obtained from 4 (95%

4- (bromomethyl) -3-fluorobenzenesulfochloride

SC, CI

20.9 g (0.1 mol) of 3-fluoro-4-methylbenzenesulfochloride are added to 200 ml of carbon tetrachloride and after the addition of 19.6 g (0.11 mol) of N-bromosuccinimide and 0.3 g of dibenzoyl peroxide, the reaction mixture is heated for 5 hours under reflux. After cooling, the solid was filtered off and the filtrate was freed from solvent. Flash chromatography (petroleum ether / toluene 4: 1) gave 12.4 g (44%) of the title compound.

Rf = 0.42 (petroleum ether / toluene 3: 1).

Example XVI

4- (Sromomethyl) -3-trifluoromethylbenzenesulfochloride

3r-H ₂ C — SO ₂ Cl r- ₃ C

64.6 g (0.1 mol) of 3-trifluoro-4-methylbenzenesulf chloride are added to 500 ml of carbon tetrachloride and after addition of

44.5 g (0.25 mol) of N-bromosuccinimide and 0.4 g of ABN were heated under reflux for 24 hours. After cooling, the solid was filtered off and the filtrate was freed from solvent. Flash chromatography using petroleum ether / toluene (4: 1) afforded 3.9 g (40%) of the title compound.

Rf = 0.41 (petroleum ether / toluene 3: 1).

Example XVII (S) -4- (Sromomethyl) -3-fluorobenzenesulfonyl-N-2- (tert-butoxycarbonyl) pyrrolidinide

Analogously to Example III, it is obtained from

8.6 g (30 mmol) of the compound of Example XV and 5.1 g (30 mmol) of S-proline-tert-butyl ester 12.7 g (100% of theory) of the title compound.

Rf = 0.57 (petroleum ether / ethyl acetate 7: 3).

Example XVIII (S) -4- (Sromomethyl) -3-trifluorobenzenesulfonyl-N-2- (tert-butoxycarbonyl) pyrrolidinide

Analogously to Example III, it is obtained from

16.9 g (50 mmol) of the compound of Example XVI and 8.6 g (50 mmol) of S-proline-tert-butyl ester 23.6 g (100% of theory) of the title compound.

Rf = 0.63 (petroleum ether / ethyl acetate 7: 3).

Example XIX (S) -4- (Arboxy-3-hydroxybenzenesulfonyl-N-2- (tert-butoxycarbonyl) pyrrolidinide

Analogously to Example III, it is obtained from

23.7 g of 4-carboxy-3-hydroxybenzenesulfochloride (100 mmol) and 17.1 g (100 mmol) of S-proline-tert-butyl ester 30.0 g (81% of theory) of the title compound.

Rf = 0.18 (acetone).

Example XX

(S) -4-Benzoyloxycarbonyl-3-benzyloxy-sulfonic acid N-2- (tert-butoxycarbonyl) pyrrolidinide

25.3 g (68 mmol) of the compound of Example XIX are dissolved in 200 ml of dimethylformamide and treated with 28.3 g of potassium carbonate (204 mmol) and 25.7 g (150 mmol) of benzyl bromide. The reaction mixture was then allowed to stir for two hours at 75 ° C, after cooling, one liter of water was added and extracted three times with 400 ml of ethyl acetate each time. The combined extracts were washed with water (5 x 400 mL), dried over anhydrous magnesium sulfate, filtered, and the volatiles were removed in vacuo. Purified by flash chromatography (petroleum ether / dichloromethane 5: 1 and petroleum ether / ethyl acetate 6: 1, grain size). 50 pm). For further purification, the product was crystallized from 600 ml of a solvent mixture (petroleum ether / ethyl acetate 6: 1) to give 35.5 g (95% of theory) of the title compound.

Rf = 0.53 (petroleum ether / ethyl acetate 7: 3).

Example XXI

(S) Dicyclohexyl) -3-benzyloxybenzenesulfonic acid N-2- (tert-butoxycarbonyl) pyrrolidinide

11.03 g (20 mmol) of the compound of Example XX are dissolved in 100 ml of diglycene and, after addition of 1.51 g (40 mmol) of sodium borohydride and 1.68 g (40 mmol) of lithium chloride, the reaction mixture is stirred for 4 hours at temperature 70 ° C. After cooling, the reaction mixture was treated with 500 ml of water and acidified to pH 3 with 1 N hydrochloric acid. It is then extracted with diethyl ether (3 x 300 ml), washed with water (6 x 300 ml), the organic phase is dried over anhydrous magnesium sulphate and the filtrate is freed from the solvent. The residue is chromatographed on silica gel 60 F 254 using a 7: 3 mixture of petroleum ether and ethyl acetate. The corresponding fractions are concentrated and dried. 5.0 g (56% of theory) of the title compound are obtained.

Rf = 0.36 (petroleum ether / ethyl acetate 7: 3).

Example XXII

(S) -4-3-Methyl-3-benzyloxybenzenesulfonic acid N-2- (tert-butoxycarbonyl) pyrrolidinide

O

CH ₂

2.24 g (5 mmol) of the compound of Example XXI are introduced into 20 ml of absolute dimethylformamide under a protective gas atmosphere. At 0 ° C, 2.53 g (6 mmol) of triphenylphosphine dibromide are added and the reaction mixture is stirred for one hour at room temperature. It is then treated with 200 ml of water, extracted with ethyl acetate (3 x 80 ml), washed with water (5 x 60 ml), dried over anhydrous magnesium sulfate, filtered and the volatiles are removed in vacuo. Purify by flash chromatography (dichloromethane, 50 µm particle size) to give 2.55 g (100% of theory) of the title compound.

Rf = 0.56 (petroleum ether / ethyl acetate 7: 3).

Manufacturing examples

Example 1 rac. 4- {2-Butyl-imidazo [4,5-b] pyridin-13-yl} -methyl-3-chloro-benzenesulfonyl-N- (2-tert-butoxycarbonyl) -piperidinide

2.3 g (5 mmol) of the compound of Example VIII, dissolved in 8 ml of dimethylformamide, were added to a solution of 613 mg (3.5 mmol) of 2-butylimidazo [4,5-b] pyridine and 105 mg (5.5 mmol) of sodium hydride. and the reaction mixture was stirred for 3 hours at 20 ° C. The reaction mixture was then poured onto ice, extracted with ethyl acetate (3 x 50 ml), washed with saturated sodium chloride solution (5 x 50 ml), dried over anhydrous magnesium sulfate, filtered, and all volatiles were removed in vacuo. . The residue obtained is purified by flash chromatography (dichloromethane / ethyl acetate 20: 1, particle size 50 pm) and the product obtained is chromatographed on silica gel (ethyl acetate / petroleum ether 1: 1, particle size 50 pm) to give 563 mg (30% of theory). of the title compound.

Melting point = 0.72 (ethyl acetate / petroleum ether 2: 1).

Example 2 rac. 4 - [{2-Flutyl-imidazo [4,5-bpyridin] -3-ylmethyl-3-chlorobenzenesulfonyl-N- (2-carboxy) piperidinide

S0 ₂ -N

273 mg (0.5 mmol) of the compound of Example 1 were dissolved in 10 ml of dichloromethane and treated with 2 ml of trifluoroacetic acid. The reaction mixture was stirred for 3 hours at 20 ° C and then all volatiles were removed in vacuo. The residue is taken up in 20 ml of a 1: 1 mixture of dichloromethane and diethyl ether and then concentrated to dryness in vacuo. This process was repeated three times to give 300 mg (99% of theory) of the title compound as the trifluoroacetate salt.

Rf = 0.30 (dichloromethane / methanol 10: 1).

The compounds listed in Tables 1, 2 and 3 were prepared analogously to the previous examples.

The following movable phases are used for the Rf values given in the following tables:

a = methylene chloride / methanol 10: 1 b = petroleum ether / ethyl acetate 1: 1 c = ethyl acetate / petroleum ether 2: 1 d = methylene chloride / methanol 4: 1 e = toluene / methanol 10: 1

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Example 20

S-4 - [{2- Phthyl-imidazo [4,5-b-S, 7-dimethyl-pyridin} -3-ylmethyl-3-chloro-benzenesulfonyl-N- (2-methoxycarbonyl) -pyrrolidinide

296 mg (0.5 mmol) of the compound of Example 29 (see Table 4), dissolved in 5 mL of dimethylformamide, was sequentially treated with 345 mg (2.5 mmol) of potassium carbonate and 99 mg (0.7 mmol) of methyl iodide. The reaction mixture was stirred for 10 minutes at 20 ° C and treated with 30 mL of water and 3 mL of 1 N hydrochloric acid. It is then extracted with ethyl acetate (3 x 50 ml), the combined organic phases are washed with water (5 x 50 ml), dried over anhydrous magnesium sulfate, filtered and all volatiles are removed in vacuo. 211 mg (86% of theory) of the title compound are obtained.

Rf = 0.67 (dichloromethane / methanol 10: 1) configuration: S.

Examples 21 and 22

S-4 - [{2-Sutyl-imidazo [4,5-bp.-5,7-dimethyl-pyridin} -3-ylmethyl-3-chloro-benzenesulfonyl-N- (2-carboxy) -pyrrolidinide (example 21)

1.0 g (1.62 mmol) of the compound of Example 47 (see Table 4) is vigorously stirred with 300 ml of pH ~ buffer solution and 150 ml of chloroform for 30 minutes at 20 ° C. The organic phase was separated and the aqueous phase was extracted with chloroform (4 x 50 mL). The combined organic phases were washed with water (2 x 100 mL), dried over anhydrous magnesium sulfate, filtered, and all volatiles were removed in vacuo. After drying in vacuo, 0.70 g (86%) of the title compound is obtained (Example 21). Configuration: S.

Potassium 4- [{2-butyl-imidazo [4,5-b] -5,7-dimethyl-pyridin} -3-yl] -methyl-3-chloro-benzenesulfonyl-N- (2-carboxy) -pyrrolidinide salt (example 22)

334 mg (0.66 mmol) of the compound of Example 21, dissolved in 5 mL of methanol, was treated with 43 mg (0.66 mol) of 85% powdered potassium hydroxide. Volatile components were removed in vacuo to give 35 mg (100% of theory) of the title compound after drying as the potassium salt (Example 22).

Configuration: S

The compounds listed in Table 4 were prepared by analogy to that described in Examples 20-22.

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The T352

Analogously to Example 1, 2.08 g (60% of theory) of the title compound are obtained from 3 g (4.62 mmol) of the compound of Example XIV.

Rf = 0.0.46 (petroleum ether / ethyl acetate 1: 1).

Analogously to Examples 1 and 2, the compounds shown in Table 5 are prepared.

Claims (10)

Sulfonylbenzyl-substituted imidazopyridines of the general formula I in which · R ³ represents straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, which are optionally substituted by cycloalkyl having 3 to 6 carbon atoms or cycloalkyl having 3-3 carbon aromatics, 3 and D together form a heterocyclic radical of formula R ₂ 'N * 4 * 4, N. .R, r ₄ or R in which R ² and R ³ are identical or different and represent hydrogen, halogen or straight-chain or branched alkyl having up to 8 carbon atoms, R ⁴ has the abovementioned meaning ^of R and R and are identical to or different from this, or represents a group -CO-R ^6, wherein R ⁶ represents a hydroxy group, a straight or branched alkoxy group having up to 8 carbon atoms, a phenoxy group, a benzyloxy group or an -NR ⁷ R ^{8 group} , wherein: R ⁷ and R ⁸ are the same or different and denote a hydrogen atom, a straight or branched alkyl group of up to 6 carbon atoms or a phenyl group, R ⁵ represents a hydrogen atom, a halogen atom, a straight or branched alkyl group of up to 8 carbon atoms, or a straight or branched perfluoroalkyl group of up to 6 carbon atoms, or a group of the formula -ΟΧ, wherein: X represents a hydrogen atom, a hydroxy protecting group or a straight or branched alkyl group of up to 8 carbon atoms, and A denotes a 3 to 8 membered saturated heterocycle with up to 2 additional heteroatoms selected from the group consisting of sulfur, nitrogen or oxygen, which is optionally up to twice the same or differently substituted by a perfluoroalkyl group of up to 5 carbon atoms or a radical of formula -CO-R something Η, η KOR- *) (OR- ⁴ ), where Q R represents a hydrogen atom, a straight or branched alkyl group having up to 6 carbon atoms, or a triphenylmethyl group, R ¹⁰ is as defined above for R ⁶ and is the same or different with R ⁶ 11 12 R and R are the same or different and represent a hydrogen atom, a straight or branched alkyl group of up to 8 carbon atoms or a phenyl group, and salts thereof. The sulfonylbenzyl-substituted imidazopyridines according to claim 1, in which R @ ¹ denotes a straight or branched alkyl or alkenyl group having in each case up to 6 carbon atoms optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or cyclopropyl, cyclopentyl or cyclohexyl, B and D together represent a heterocylic radical of the formula in which R ² and R ³ are the same or different and represent a hydrogen atom, a fluorine, chlorine or bromine atom, or a straight or branched alkyl group of up to 6 carbon atoms, and R ⁴ has the meaning stated for R ² and R ³ and is identical to or different from this, or represents a group of formula -CO-R ^6, wherein R ⁶ represents a hydroxy group, a straight or branched alkoxy group having up to 6 carbon atoms, a phenoxy group, a benzyloxy group or a group of the formula -NR ⁷ R ⁸ , wherein: R and R ° are the same or different and are hydrogen or a straight or branched alkyl group of up to 4 carbon atoms, R represents a hydrogen atom, a fluorine, chlorine or bromine atom, a straight or branched alkyl group having up to 6 carbon atoms, or a straight or branched perfluoroalkyl group having up to 6 carbon atoms; Or a group of formula -ΟΧ, wherein: X represents a hydrogen atom, a benzyl group, an acetyl group or a straight or branched alkyl group having up to 6 carbon atoms and denotes an azetidinyl group bonded via a nitrogen atom to a piperidinyl group, a pyrrolidinyl group or a morpholinyl group optionally substituted by a trifluoromethyl group or radical -SO ₃ H, -CO-R ¹⁰ or -? (OR ¹¹ ) (OR ¹² ), N-N wherein R represents a hydrogen atom, a straight or branched alkyl group having up to 4 carbon atoms, or a triphenylmethyl group, R ^x is as defined above for R and is the same or different with R a TΠ T9 * * · R ¹ · ¹ · and R can be identical or different and denote hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or phenyl, and salts thereof. The sulfonylbenzyl-substituted imidazopyridines of claim 1, wherein: R @ ¹ denotes a straight or branched alkyl or alkenyl group of up to 4 carbon atoms or a cyclopropyl group, B and D together represent a heterocyclic radical of the formula R ₄ in which R ² and R ³ are the same or different and represent a hydrogen atom, a fluorine, chlorine or bromine atom, or a straight or branched alkyl group of up to 4 carbon atoms, and R ⁴ has the meaning stated for R ² and R ³ and is identical to or different from this, or represents a group of formula -CO-R ^6, wherein R ⁶ denotes a hydroxy group, a straight or branched alkoxy group having up to 4 carbon atoms, a phenoxy group, a benzyloxy group or a group of the formula -NR ⁷ R ⁸ , wherein: R and R ° are the same or different and are hydrogen or a straight or branched alkyl group of up to 3 carbon atoms, R represents a hydrogen atom, a fluorine or chlorine atom, a straight or branched alkyl group of up to 4 carbon atoms, or a straight or branched perfluoroalkyl group of up to 3 carbon atoms, or a group of the formula -ΟΧ, wherein: X represents a hydrogen atom, a benzyl group, an acetyl group or a straight or branched alkyl group of up to 5 carbon atoms, and A represents an azetidinyl group bonded via a nitrogen atom with a piperidyl group or a pyrrolidinyl group, which are optionally substituted with a trifluoromethyl group or a radical of formula s for ₃ h N z- \ N \ Oí — í -CO-R ¹⁰ or -P (OR ¹¹⁾ (OR ^12), N-N wherein Q. , R represents a hydrogen atom, a methyl group, an ethyl group or a triphenylmethyl group, τ n 6 R is as defined above for R and is the same or different with R a * 1 1 9 R and R 6 may be the same or different and represent a hydrogen atom, a straight or branched alkyl group of up to 4 carbon atoms or a phenyl group, and salts thereof. The sulfonylbenzyl-substituted imidazopyridines of claim 1 for therapeutic use. 5. A process for the preparation of sulfonylbenzyl-substituted imidazopyridines according to claim 1, characterized in that the sulfonylbenzyl compounds of the general formula II are reacted. H ₂ C 5 * so ₂ -a (W in which A and R ^{5 are} as defined above, and L represents a halogen atom, preferably bromine, with the imidazopyridines of the general formula III N- / HN - (ΠΙ) in which R ¹ , B and D are as defined above, in inert solvents and in the presence of a base and both the substituents R ¹ and R ⁵ as well as the heterocyclic rings (A, B, D) may optionally be converted by by conventional methods such as alkylation or saponification. A medicament comprising at least one sulfonylbenzylsubstituted imidazopyridine according to claim 1. A process for the preparation of medicaments according to claim 6, characterized in that the sulfonylbenzyl-substituted imidazopyridines are converted into a suitable dosage form, optionally using excipients and carriers. Use of the sulfonylbenzyl-substituted imidazopyridines according to claim 1 for the manufacture of medicaments. 9. Sulfonylbenzyl compounds of the general formula II ⁿ 5 lh ₂ c - < so ₂ -a (H) wherein A and R 6 are as defined above, and L represents a halogen atom. 10. A process for the preparation of sulfonylbenzyl compounds of the general formula II 1h ₂ c * 5 so ₂ -a (ID in which R and L denoting the compounds of the general formula as defined above are reacted with LH ₂ C ₂ -ci (IV ') in which L and R ^{5 are} as defined above, with compounds of formula V A - Η (V) in which A is as defined above, in an inert solvent and in the presence of a base / ((? 0 Formula for annotation (I))